A BOILOGICAL ANALYSIS OF CANCER: A CRITICAL

STUDY
A
Project
Submitted to the

Bundelkhand University
in partial fulfillment of the degree of
Bachelor of Pharmacy

2021-2022

UNDER THE SUPERVISION

Guide by Submitted by:

Dr. SUNEEL KUMAR NIRANJAN RAHUL SHARMA
Assistant Professor B.Pharmacy 4th Year
B.U. Jhansi (U.P) Roll No.181251016041

INSTITUTE OF PHARMACY BUNDELKHAND UNVERSITY

JHANSI (U.P.)
 INSTITUTE OF PHARMACY
BUNDELKHAND UNIVERSITY , JHANSI

2021-2022

CERTIFICATE

This is to certify that the project report entitled ‘’A Biological Analysis of
Cancer: A critical Study” submitted in partial fulfillment of the
requirement for the degree of bachelor of pharmacy, Institute of
Pharmacy Bundelkhand University , Jhansi is a bonafied work carried out
by RAHUL SHARMA during the academic session 2021-2022.

Date; H.O.D.
Dr. PEEYUSH
BHARDWAJ
Head of Department
Institute of pharmacy
B.U, Jhansi
 INSTITUTE OF PHARMACY
BUNDELKHAND UNIVERSITY , JHANSI

2021-2022

CERTIFICATE

This is to certify that the project report entitled ‘’A Biological Analysis of
Cancer: A critical Study” submitted in partial fulfillment of the
requirement for the degree of bachelor of pharmacy, Institute of
Pharmacy Bundelkhand University , Jhansi is a bonafied work carried out
by RAHUL SHARMA during the academic session 2021-2022.

Date; Guide by

Dr. SUNEEL KUMAR

NIRANJAN
Asssistant Professor
Institute of Pharmacy
Bundelkhand University, Jhansi
 INSTITUTE OF PHARMACY
BUNDELKHAND UNIVERSITY , JHANSI

2021-2022

DECLARATION

I hereby declare that this project entitled “A boilogical Analiysis of

Cancer: A critical Study” is prepared by me under the direct guidance
and supervision of Dr. SUNEEL KUMAR NIRANJAN Institute pharmacy,
Bundelkhand University, Jhansi. The same is submitted to Bundelkhand
University ,Jhansi in partial fulfillment of requirement for the award of
the degree of Bachelors of Pharmacy .I further declare that I have not
submitted this project previously for the award of any degree or diploma
to me.

RAHUL SHARMA
 ACKNOWLEDGEMENT

I got excellent opportunity to carry out my project under the supervision of Dr.
SUNEEL KUMAR NIRANJAN institute of pharmacy Bundelkhand University,
Jhansi, who supervise this project work and whose expert guidance, supervise
timely suggestion, explicit decision, deep personal interest and attention
which theyshow keenly has been a privilege for me.

I owe special thanks for the motivation, inspiration and support in boosting my
moral without which I would have been in vain.

RAHUL SHARMA
 CONTENTS
S. No. Title Page No
1. Introduction 1
2. Types of Tumors 1
3. Types of Cancers 1
4. 3
Causes Of Cancer
5. 3
Characteristics Of Cancer Cells
6. 3
The Cell Cycle And The Checkpoints
7. How Cancer Arises? 6

8. 7
Some Genes Involved In Human Cancers

9. 8

Tumor Suppressor Genes

10. Genes for Proteins in the Nucleus 9

11. Anticancer Drugs 9

12. 10
Classification Of Anticancer Drugs

13. 11

Individual Drugs
14. Platinum Coordination Complexes 14

15. Antimetabolites 15

16. Folic Acid Analogoues 15

17. Pyrimidine Antagonist 16

18. Microtubule Damaging Agents 18

19. Targeted Drugs 20
20. The Main Step Of Anticancer Drug 21
21. Agent Of Cancer 22
22. Treatment Of Cancer 23
23. Problems With Cancer Chemotherapy 23

24. Limitation Of Chemotherapy 23

25. Toxicity Of Cytotoxic Drugs 24

26. Strategies And Materials Used In Cancer Therapy 25

27. 25

Conclusion

28. 26
References
 TABLE OF FIGURES
Figure No. Title Page No.
Fig. 1 Basal Cell Carcinoma 2
Fig.2 Squamous Cell Carcinoma 2
Fig.3 Transitional Cell Carcinoma 2
Fig.4 The Cell Cycle and Check Point 4
Fig.5 Effects of Chemotherapeutic Agents on The Growth Cycle of 5
Mammalian Cells
Fig.6 Cell Cycle Non-Specific Drugs 6
Fig.7 Tumor Development Occur in Stage 7
Fig.8 Mechanisms of Action of Alkylating Agent 12
Fig.9 Mechanism of Action Methotrexate 16
Fig.10 Structure of Vinca Alkaloid 19
Fig.11 Mechanism of Action of Vinca Alkaloids 19
Fig.12 Carcinogenesis Agents 22
INTRODUCTION
Cancer arises as a result of the uncontrolled growth of malignant cells, which have the
probability to invade or spread to other body part. Cancer is one of the world’s most
terrifying disease evaluating more than 10 million new cases each year after a better
understanding of tumor biology and improvement in diagnostic devices and treatment the
mortality rate thus has decreased in the past 5 years. Surgical intervention, Chemotherapy,
and radiation therapy or a combination of these is basic treatments to treat Cancer nowadays.
The treatment is frequently used to kill healthy cells and causes toxicity and side effects to
the patient.

A different type of approaches is being practiced for the treatment of cancer of which
everyone contains significant limitation and a side effect in cancer, there uncontrolled
proliferation of cells where apoptosis is greatly vashed and it also, require very complex
process of treatment. The most common treatment includes chemotherapy, in which
anticancer drugs are provided to patients for suppressing the unregulated proliferation of
cancerous cells. Cancer therapeutic is the difference between the cancerous cells and the
normal body cell is the main challenge that scientist working on it has to overcome and also
cancer drug development requires a very complex procedure. So, the main object is to
engineer a drug in such a way that it can identify the cancer cells to lower their growth and
proliferation.

Types of Tumors
All tumors are not cancerous; tumors can be benign or malignant. Benign tumors are not
cancerous. They can often be removed and they do not come back, and the cells in benign
tumors do not spread to other parts of the body. Malignant tumors are cancerous; cells in
these tumors can invade nearby tissues and spread to other part of body. The spread of cancer
from one part of the body to another is called metastasis.

Benign Malignant

Slow growing Fast growing

Capsulated Non capsulated
Suffix ‘’oma’’eg.Fibroma Suffix ‘’carcinoma’’ or
‘’sarcoma’’

Types of cancer
On the basis of origin-
Carcinoma-Skin / tissues that line or cover internal organs like stomach, liver colon or breast
.most common tumors are carcinoma including adenocarcinoma basal cell carcinoma,
squamouscell carcinoma.

1
Fig1.Basal cell carcinoma

Fig2

Fig3Transitional cell carcinoma

Sarcoma- These cancers begin in fat, bone, cartilage, blood vessels, and muscle. They can
also be found connective or nerve. They originate in outside the bone marrow.

Leukemia- Leukemia is a cancer of the bone marrow and causes larger numbers of abnormal
blood cells and most common in childhood.

Lymphoma and myeloma-These cancers begin in immune system and plasma cells.

2
 CNS nervous system- cancers that begin in the tissues of the brain and spinal cord.

Germ cell cancer- These cancers begin in testicle and ovarian cancers.

Causes of cancer

 Environmental factors 90-95%

 Radiations
 Smoking and alcohol
 Infections, obesity
 Chemical

Characteristics of cancer cells-

The basic differences between cancer T-cells and normal cells are:

• Cancer involves the development and reproduction of abnormal cells.

• Cancer cells are usually non-functional.

• Cancer cell growth is not subject to normal body control mechanisms and

• Ability to invade surrounding tissues and (metastasize) to other organs via the circulatory
lymphatic systems.

The Cell Cycle and the Checkpoints

1-Cell Growth Checkpoint

 Occurs toward the end of growth phase 1(G1).

 Check whether the cell is big enough and has made the proper protein for the synthesis.
 If not, the cell goes through a resting period ((G0) until it is ready to divide.

2- DNA Synthesis Checkpoint

 Occurs during the synthesis phase(s).

 Checks whether DNA has been replicated correctly
 If so, the cell continues on the mitosis

3- Mitosis Checkpoint

 Occurs during mitosis phase (M).

 Check whether mitosis is complete
 If so, the divides and the cycle repeal.

3
 Mitosis (nuclear division) and
cytokines (cell division) yield
two daughter cells

Mitosis
RNA and protein checkpoint
synthesis continue.no
DNA synthesis Synthesis mRNA and
protiens(known as histones) that are
required for DNA synthesis

G0

Resting

Synthesis or replication of DNA

Cell Growth Checkpoint

DNA synthesis
checkpoint

Fig4 the Cell Cycle and Check point

4
 A. The cell cycle

(Effects of chemotherapeutic agents on the growth cycle of mammalian cells)

B. Cell cycle specific drugs Fig5

Antimetabolites Bleomycine peptide antibiotics

Vinca alkaloids Etoposide

Effective for high growth fraction malignancies, e.g., hematologic cancer.

C. Cell Cycle Non Specific Drugs

Alkylating agent antibiotics cisplatin, nitrosources

Effective for both low growth fraction malignancy e.g. solid tumors.

5
 Fig6: Cell Cycle Non-Specific Drugs

How cancer arises?

Honestly, the term ‘’cancer’’ refers to more than 100 form of disease.

Almost all the tissues of body show malignancy. All type of cancer show the peculiar
features. Still the main process that produce these diverse tumors appear be quite similar.

The 30 trillion normal healthy body cells live in complex, interdependent condominium,
regulating one other proliferation.

Actually normal cells reproduce only when instructed so by other cells in their presence.

Such unceasing collaboration ensure that each tissue maintain size and according to one's
body, Needs on the other hand cancer cells violate this form of collaboration they are

6
unaffected by the surrounding cells proliferation and follow their own pattern of division /
reproduction. They have a more dangerous property of the ability to migrate from the site of
their origin and invading

Nearby tissue, forming new tumors at new sites of the body, such tumors pose real threat to
body as they become more and more aggressive over time. As a result of which they become
lethal to the surrounding tissues and organs needed for on undivided to survive as a whole.
Genes are carried in the DNA molecules of the chromosome in the cell’s nucleus. A gene is
formed by a sequence of amino acids that are linked together to make a particular protein.
The protein then performs function of a gene. These genes encode protein When mutation
occurs a gene may change its form and activity eventually changing protein product. Two
genes which together make a small part of genetic set are major reasons in triggering cancer.

Fig7 (Tumor development occur in stage)

The mainly decide the pattern of cell reproduction and growth. Proto-oncogenes tumor
suppress or gene inhibits it. After mutation, proto- oncogenes can become carcinogenic
oncogenic that gives rise to excise multi placation. The mutation may for too much of it have
encoded growth stimulatory protein or an overly active form of it. At the same time tumor
suppressor gene contribute by mutation as a result of which function suppressor proteins
deprive of curvial brake that prevent in appropriate growth.

Some genes involved inhuman Cancers

Genes code for protein called proto-oncogenes that activate cell division mutated form allied
oncogenes, cause the stimulatory proteins to be hyperactive, the result that cells proliferate
overly. Tumor suppressor genes code for protein that block cell division. Mutation can cause
the proteins to be inactive and may thus deprive cells of needed restraints on proliferation.

7
Investigators are still trying to decipher the specific function of many tumor suppressor
genes.

Genes for Growth Factors or Their Receptors

PDGF- Codes for platelet, derived growth factor. In glioma (a brain cancer) PDGFare
involved.
Erb-B -Codes for the receptor for epidermal growth factors, which is involved in
glioblastoma (a brain cancer) and breast cancer
erb-B2- Another name of erb-B2 is HER-2 and neu. Codes for growth factor receptor these
are involved in breast, salivary gland and ovarian cancer.
RET- Codes for growth factor receptor. Involved in thyroid cancer.

Genes for cytoplasm relays in stimulating signaling pathways

Ki-ras- Lung, ovarian, colon and pancreatic cancers.

N-ras- It involved in leukemia’s

Genes for transcription factors that activate growth – promoting genes

c-myc- Involved in leukemia’s and breast, stomach and lung cancers

L-myc- Involved in lung cancer
N-myc- Involved in neuroblastoma (a nerve cell cancer) and glioblastoma

Genes for other kinds of molecule

Bcl2- Codes for a protein that normally blocks cell suicide. Involved in follicular B cell
Lymphoma.

Bcl-1- Also called PRAD1. Codes for cyclin D1, a stimulatory component of the cell cycle
clock. Breast head and neck cancer due to Bcl-1.
MDM2-Codes for an antagonist of the p53 tumor suppressor protein. Involved in sarcomas
(connective tissue cancers) and other cancers.

TUMOR SUPPRESSOR GENES-

Genes for Protein in the Cytoplasm

APC- Involved in colon and stomach cancers

DPC4- Codes for a relay molecule in a signaling pathway that inhibits cell division. Involved
in pancreatic cancer.
NF-1- Codes for a protein that inhibits a stimulatory (Ras) protein. Involved in neurofibroma
and pheochromocytoma (cancers of the peripheral nervous system) and myeloid leukemia.
NF-2- Involved in meningioma and ependymoma (brain cancers) and schwannoma (affecting
the wrapping around peripheral nerves).

8
 Genes for Proteins in the Nucleus

MTS1- Codes for the p16 protein, a braking component of the cell cycle clock. Involved in a
wide range of cancers.
RB- Codes for the pRB protein, a master brake of the cell cycle. Involved in retinoblastoma
and bone, bladder, small cell lung and breast cancer.

P53-Codes for the p53 protein, which can halt cell division and induce abnormal cells to kill
themselves. Involved in a wide range of cancer.
WT1- Involved in Wilms’ tumor of the kidney.

Genes for proteins whose cellular location is not yet clear

 BRCA1- Involved in breast and ovarian cancers.

 BRCA2-Involved in breast cancer.
 VHL- Involved in renal cell cancer.

Anticancer Drugs

The chemotherapeutic agents which are used in the treatment of cancer is called
antineoplastic agent or anticancer drugs .These drugs are used in rapidly dividing cells or
malignant disease when surgery or radiotherapy has failed to prove effective . In malignant
disease, drugs used with target.

1- Cure or prolonged remission- Acute leukemia’s, Choriocaromacinoma, Wilm’s tumor,

Hodgkin’s disease, Ewing ‘s sarcoma, Lymphosarcoma, Retinoblastoma, Burkett’s
lymphoma, Rhabdomyosrcoma, Testicular teratomas, Seminoma, Mycosis fungicides.

2- PalliationGratifying-Breast cancer, chronic lymphatic leukemia, Ovariancarcinom ,Chronic

myeloid leukemia, Endometrial carcinoma, Non-Hodgkin lymphomas, Myeloma, Head and
neck cancers, Prostatic carcinoma, Lung cancer.

3- Adjuvant chemotherapy- Cure, mainly in early breast, lung and colonic cancer.

9
CLASSIFICATION OF ANTICANCER DRUGS

Anticancer drugs (1))

Anticancer drugs- 2

10
Anticancer drugs (3)

(Classification of anticancer drugs, K.D. Triphathi, 8th volume, page no.916)

INDIVIDUAL DRUGS

Alkylating agents are compounds that are capable of introducing an alkyl group into
nucleophilic sites on DNA, RNA or any enzyme through covalent bond. These agents are
thought to react with the 7 position of guanine (or any other nitrogen base) in each of the
double strands of DNA causing cross- linking that interferes with separation, of the strands
and prevent mitosis. The effects of base alkylation include misreading of the DNA codon and
single strand breakage of the DNA chain. The long-time effects are mutation and cell death.
The favored site on DNA is at the N7 position of guanine, adenine, cytosine, and even the
sugar phosphate group.

Mechanism of alkylating agent-

The major targets of drugs action of nucleophilic groups present on DNA (especially the 7
position of guanine; proteins and RNA among other may also be alkylated. These are several
potential nucleophilic sites on DNA; which are susceptible to electrophilic attack by an
alkylating agent (N-2, N-3 and N-7 of - guanine, N-1, N-3 and N-7 of adenine, 6 of thymine,
N-3 of cytosine). The mechanism of alkylating agent occurs by the introduction of an alkyl
group at Nucleophilic site on the DNA by the covalent linkage.

This class of anticancer agent reacts with the 7 position of guanine or some other nitrogen
base in each of the double strand of DNA forming cross- linkage that interferes with the

11
separation of DNA strands and prevent mitotic phase of the cell cycle. This cause breakage of
the DNA strands, interfering the ability of Cancer cell to multiply. Eventually the cancer cell
dies.

Fig8 MECHANISMS OF ACTION

Dr. Mwatonok Joyce

12
Chemical structure of alkylating agent-

Ex.CYCLOPHOSPAMIDE-

Cyclophosphamide is a cytotoxic cell cycle nonspecific agent. It is a prodrug,

Cyclophosphamide is well absorbed orally and activated in liver. Initially the CYP-450-
enzyme catalyzed metabolic step leads to the formation of 4-hydroxycyclophosphamide, that
equilibrate with their ring-opened aldotautomers i.e. aldocyclophosphamide. The aldo
intermediates of cyclophosphamide play an important role in anti-tumor efficacy. The aldo
derivatives undergo a non-enzymic β-elimination of toxic and nephrotoxic acrolein to yield
the ultimate alkylating species.

13
Mechanism of Cyclophoasphamide-
Liver CYP 286

CYCLOPHOSPHAMIDE 4-OHcyclophosphamide

All tissues spontaneous

Beta-elimination of toxic and
nephrotoxic acrolein

aldophosphamide
Liver non
All tissue microsomal
spontaneous

other alkylating metabolites

Acrolein + phosphoramide

mustard

Pharmacokinetic-cyclophosphamide is administered by orally or IV, metabolites in liver,

excreted in the urine as unchanged drug.

USES- Leukemia, lymphosoma, rheumatoid arthritis, multiple sclerosis (disease of the brain
and spinal cord (central nervous system).

PLATINUM COORDINATION COMPLEXES

The platinum coordination complexes is enter the cells and hydrolyzed intracellular and
produce a highly reactive moiety. Due to highly reactive moiety cause cross linking of DNA.

Cisplastin- Cisplastin is a member of platinum coordination complex. Cisplastin is more

effective for testicular and ovarian sarcoma. these are used in another solid tumor. Non cell
cycle specific killing. Highly bound to plasmas proteins, poorly penetrate blood brain barrier,
slowly excreted in urine.

14
MECHANISM OF ACTION

Cisplastin enters the cells

Cl-

Complexes Forms highly reactive platin

Intra strand & interstrand cross links

DNA damage

Inhibits cell proliferation

Pharmacokinetics- Administered by i.v. Concentration of drugs found in testicular ovarian &

kidney, excreted by urine metabolize in liver.

Uses- lungs cancer, bladder cancer, stomach cancer etc.

ANTIMETABOLITES

Antimetabolites are the agents that interfere with the synthesis of the DNA constituents
(normal cellular metabolites). These agents are similar in structure to the metabolites (purine
and pyrimidine bases or corresponding nucleosides), or folate cofactors which are essential
for cell growth and division. Due to structure similarities between antimetabolites with lular
metabolites, these agents readily incorporated in to DNA or RNA and interfere with cellular
function. For e.g. antifolate competitively inhibits the folic acid and produce toxic effect
on cells i.e. they stop the cell division and growth.

Most of the antimetabolites are phase-specific, acting during the S-phase of the cell cycle
(cell-cycle specific) when DNA replication is occurring.

Folic acid analogues

Folic acid is synthesis of nucleic acid (DNA and RNA). It is converted by enzyme
dihydrofolate reductase in to tetrahydrofolic acid. THF is necessary for the synthesis of
precursors of DNA (Thymidylate and purines) and RNA (Purines) and some amino acids.
Folic acid analogues or antifolates competitively inhibits the enzyme dihydrofolate reductase
and prevent synthesis of THF and ultimately inhibit the synthesis of DNA.

15
 Methotrexate (Mtx) -Mtx is a folic acid analogue. Highly efficacious antineoplastic drugs.

Mechanism of action- Methotrexate potentially inhibits dihydrofolate reductase

(DHFR).This leads to decrease production of compounds adenine, guanine and thiamidine
and the amino acids methionine and serine, depletion of thymidine. Finally interfere DNA,
RNA, and protein synthesis and ultimately leads to cell death.

Uses; Acute lymphocytic leukaemia Fig9 (Mechanism of action methotrexate)

• Prophylaxis in meningeal leukaemia (brain and spinal cord)

• Choriocarcinoma ( uterus)

• management of breast cancer

• osteocarcinoma

ADR-Ulcerative stomatitis, Leukopenia, Abdominal distress

PYRIMIDINE ANTAGONIST

The pyrimidine blocks in the synthesis of DNA and RNA nucleotides. In the replication
process these nucleotides combine to form DNA strands. The pyrimidine analogues are the
compounds that inhibit the enzyme thymidylate synthetase, enzyme responsible for
conversion of 2’-deoxyuridylic acid to thymidylic acid for DNA synthesis. In other words
these agents block the action of thymidylate synthetase and inhibit the DNA synthesis.
Synthesis of dTMP from dUMP is catalyzed by thymidylate synthase. This enzyme
methylates dUMP at the 5-position to create dTMP; the methyl donor is the one-carbon folic
acid derivative N5, N10-methylene-THF. The THF cofactor is oxidized at the expense of
methylene reduction to yield dihydrofolate, or DHF. Dihydrofolate reductase then reduces
DHF back to THF for service aain as a one-carbon vehicle.
16
Fluorouracil-
It is a pyrimidine analogue containing a fluoride atom at position 5 in the ring. It principally
acts on thymidylate synthase (TS) enzyme. It interferes with DNA synthesis by blocking the
thymidylate synthetase conversion of deoxyuridylic acid (dUMP) to thymidylic acid (dTMP).

Fluorouracil and its metabolites possess a number of different mechanisms of action. In vivo,
fluorouracil is converted to the active metabolite 5-fluorouridine monophosphate (F-UMP);
replacing uracil. F-UMP incorporates into RNA and inhibits RNA processing, thereby
inhibiting cell growth. Another active metabolite, 5-5-fluoro-2'-deoxyuridine-5'-O-
monophosphate (F-dUMP), inhibits thymidylate synthase, resulting in the inhibition of
formation of dTMP. Which leads to inhibition of DNA synthesis?

Mechanism of action-Intracellular converts to;

5- flurouridine monophasphate- incorpate in RNA impairing its function and its

polyadenylation.5- fluorodeoxyuridine phosphate (5-Fd UMP) which competes with deoxy
uridine monophosphates(dUMP) for the enzyme THYMIDYLATESYNTHETASE-
negative production of dTMP- so no thymine nucleotide form- negative of DNA synthesis
through’’ THYMINELESS DEATH’’

Uses- An antineoplastic agent to treat multiple solid tumours including colon, rectal, breast,
gastric, pancreatic, ovarian, bladder and liver cancer.

Purine Analogues- are mercaptopurin, thioguanine and azathiprin. The structure of these
analogues is similar to hypoxanthine and guanine. These analogues have sulfhydryl/ thiol
group at position 6 of the purine ring instead of oxygen.

The antineoplastic activity of purine analogues depends upon the relative rates of enzymatic
activation and inactivation of these compounds in various cells and tissues. 6-mercaptopurine
is converted in to its active ribonucleotide (6-MPMP) i.e.,6- Thioinosinate by the enzyme
HGPRT. This nucleotide is potent inhibitor of glutamine amidophospho ribosyl transferase
which converts 5- phosphoribosyl pyrophosphate in to 5- phosphoribosylmine (initial step for
the synthesis of basic purines).

6- Mercaptopurine • These are highly effective antineoplastic drugs. 6-Mercaptopurine is the

thiol analog of hypoxanthine. 6-MP and 6-thioguanine were the first purine analogs to prove
beneficial for treating neoplastic disease (Azathioprine, an immunosuppressant, exerts its
cytotoxic effects after conversion to 6-MP). Purine antagonist used for the treatment of
malignant diseases (mercaptopurine, thioguanine), but also for immunosuppressant
(azathioprine) and antiviral chemotherapy (acyclovir, ganciclovir, vidarabine, and
zidovudine).

17
 Mechanism of action: 6-MP inhibit the conversion of inosine monophosphate to adenine
and guanine nucleotides that are building blocks for RNA and DNA.

1. Nucleotide formation: 6-MP converted to the nucleotide analog, 6-MPribose

phosphate (6-thioinosinic acid, or TIMP)

2. Inhibition of purine synthesis: TIMP can inhibit the first step of de novo purine-ring
biosynthesis

3. Incorporation into nucleic acids: TIMP is converted to thioguanine monophosphate

(TGMP), which after phosphorylation to di- and triphosphates can be incorporated into RNA.
The deoxy-ribonucleotide analog that are also formed are incorporated into DNA. This
results in non-functional RNA and DNA.

Uses-Mercaptopurine is used primarily for the maintenance of remission in patients with

acute lymphocytic leukemia and is given in combination with MTX for this purpose.

Adverse Effects: Well, tolerate.

Myelosuppression is generally mild with thioguanine Long-term mercaptopurine use may
cause hepatotoxicity.

Microtubule Damaging agents-

Vinca alkaloids-

The anti-cancer agents derived from plant sources are the vinca alkaloids. These compounds
made from the periwinkle plant (catharanthus roseus). There are four types of plant products
used as anticancer agents. These ares-

 Vinca alkaloid (vincristine, vinblastine, and vinorelbine)

 Epipodophyllotoxins (Etoposide and Tenoposides)
 Taxanes (Paclitaxel)
 Camptothecin derivatives (Camptothecin and irinotecan)

Vinca alkaloids have complex structures composed of indole and catharanthin moiety. The
main alkaloids that have related anticancer activity are Vincristine, vinblastine, the two of
this vincristine and vinblastine is important clinical agents for the treatment of lymphomas,
leukemias, and testicular cancer. The vinca alkaloids are cell-cycle-specific agents and block
the mitosis with metaphase arrest. The vinca alkaloids specifically bind to β-tubulin and
block its ability to polymerize with α-tubulin in to microtubules.

18
 Fig10Structure of vinca alkaloid

Mechanism of action-

Tubulin is the protein that polymerizes into long chains or filament that form microtubules.

Microtubules have the ability to undergo mitosis.

Fig11 mechanism of action of vinca alkaloids

Antibiotics-Antibiotics obtained from microorganism and have prominent antitumor

activity. All of them intercalate between DNA strands and interfere with its template
function. Eg.-Actinomycin D.

19
Actinomycin- The actinomycin are a group of compounds that are isolated from various
species of streptomyces. The 1 st drugs from this group are actinomycin D, which is known as
Dactinomycin. Other pilamycin.

Bleomycin-
Bleomycins were discovered in 1966 by H. Umezawa as fermentation products of
Streptococcus verticillus. Bleomycin refers to a mixture (bleomycin A2 and bleomycin B2) of
glycopeptides containing a pyrimidine chromophore linked to propionamide, a b-
aminoalanine amide side chain, and the sugars L-glucose and 3-O-carbamoyl-D-mannose. A
tripeptide chain and a terminal bithiazole carboxylic acid are attached to this structure; this
latter segment binds to DNA. Bleomycin has the unique feature of forming complexes with
Fe2+ while also bound to DNA. Oxidation of Fe2+ gives rise to superoxide and hydroxyl
radicals. These superoxide’s and highly reactive radicals are generated close to the DNA
double helix, and cause cleavage of the phosphodiester bonds, which results in single-strand
and double-strand breaks and inhibition of DNA biosynthesis. Bleomycin is a cell cycle-
specific drug that causes accumulation of cells in the G2 phase of the cell cycle. It is used for
the treatment of germ cell tumor, Hodgkin's and non-Hodgkin's lymphomas, squamous
(epidermis) cell cancer of the skin, cervix and vulva, head and neck cancer.

Mechanism-The drug has its greatest effect on neoplastic cell in the G2 phase of the cell
replication cycle. Although bleomycin intercalates DNA, the major cytotoxicity is believed to
result from iron catalyzed free radical formation and DNA strand breakage.

Uses; Hodgkin’s and non-Hodgkin’s lymphomas, testicular cancer, and several other solid
tumors.

Adverse Effects: Bleomycin produces very little myelosuppression. The most serious
toxicities of Bleomycin are pulmonary and mucocutaneous reactions.

Targeted Drugs-These drugs are two type -

Specific monoclonal antibodies that need to be given patently and attack cell surface targets
or tumor antigen.

Synthetic small molecular compounds, given orally which penetrates cells and affect cancer
specific enzymes or pathways. -Imatinib

Hormonal Drugs
-Hormones and related drugs are cytotoxic, but modify the growth of hormone- dependent
tumors. All hormones only palliative. Several types of hormone-dependent cancer (especially
breast, prostate, and endometrial cancer) respond to treatment with their corresponding
hormone antagonists. Estrogen antagonists are primarily used in the treatment of breast

20
 cancer, whereas androgen antagonists are used in the treatment of prostate cancer.
Corticosteroids are particularly useful in treating lymphocytic leukemia’s and lymphomas.

Estrogens:
Estrogens inhibit the effects of endogenous androgens and androgen-dependent metastatic
prostatic carcinoma. Diethylstilbestrol is usually the agent of choice. Cardiac and
cerebrovascular complications and carcinoma of the male breast are potential adverse effects.

Progestins:

Progestins are useful in the management of endometrial carcinoma and back-up therapy for
metastatic hormone-dependent breast cancer.

Androgens:

Androgen activity in breast cancer is similar to that of estrogens, perhaps for the same
mechanistic reasons. Virilizing effects and hepatic toxicity make them unacceptable to most
patients.
Fluoxymesterone is the most widely used agent.
Danazol has use in hematology in aplastic anemia and congenital anemias.

Glucocorticoids:

They are integral components of curative therapy for acute lymphoblastic leukemia, non-
Hodgkin’s lymphoma, and Hodgkin’s disease. Glucocorticoids have essential roles in the
prevention of allergic reaction, emesis control, relief of intracranial hypertension or spinal
cord compression in neurologic complications, and pain relief.

The Main Step of Anticancer Drug

Non-Clinical Research- Also called as preclinical research, study is done in animals.

1. Anticancer Drug Screen; In vitro-tumor cell culture, tumor inhibitor/kill test

In vivo-animal xenograft model e.g.Ehrlich as cites tumor, S180 lymphosarcoma

2. Pharmacodynamics, pharmacokinetics and toxicology test.

Clinical Research-A drugs should be carefully and ethically evaluated by testing in human
being for safety and efficacy. Prior to is its use in man for therapeutic purpose. Such study in
human is known as clinical trial. Clinical studies are congenitally divided into 4 phase.

1-In Phase 1 clinical trial, Determine the metabolic and pharmacodynamic effects in man.
Group of people (20-80) for the first time to evaluate its safety, determine a safe dosage
range, and identify side effects. Sample size should be 20-40.

2 -In Phase 2 clinical trials, the study drug or treatment is given to a larger group of people (40-100)
to see it is effective and to further evaluate its safety. Sample size should be 100-300.

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3 -In Phase 3 studies, the study drug or treatment is given to large groups of people (more than
200) to further determine its effectiveness, monitor side effects, compare it to commonly used
treatments, and collect information that will allow the drug or treatment to be used safety. Sample
size hundreds to thousands.

4-In phase 4 studies are done after the drug or treatment has been marketed. These studies continue
testing the study drug or treatment to collect information about their effects in various population
and any side effects associated with long term use. Sample size should be thousands.
AGENT OF CANCER-
The agent which causes cancer is called carcinogenesis. & ioning radiation is a physical agent
which causes cancer. Mutagenic effect is caused by this radiation. Ex.Luekemia Breast and lungs
cancer. Bacterial agent is a type of biological agent. Cervical cancer caused by viral agent. In
generic factors the role of generic inheritance is very important.

Fig12 Carcinogenesis agents

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 Treatment of Cancer
Chemotherapy -Rapidly dividing cell metastasized cancers (leukemia and lymphoma)

Radiotherapy- In combination with other therapies iodine -131(thyroid cancer) Iridium-

192(breast cancer).

Surgery- Not metastasized cancers prostate, breast or testicular cancer

Immunotherapy- Immune system made strong for flight against cancers

Hormone therapy- In these therapies Kill cancer cells by altering hormones levels.

Gene therapy- Replace the defected genes.

Problems with Cancer Chemotherapy

 Drug Resistance
I. De novo Resistance
II. Acquired Resistance
III. Multidrug Resistance
 Drug Toxicity

De novo resistance:

De novo resistance can be de novo genetic (i.e. the cells are initially inherently resistant), or
can arise because drugs are unable to reach the target cells because of permeability barriers
such as the blood-brain barrier

Acquired Resistance:

Acquired drug resistance may result from genomic mutations, such as the induction or
deletion of enzymes involved in drug inactivation or drug activation, respectively

Multidrug Resistance:

P-glycoprotein transports many naturally occurring drugs out of neoplastic cells, and its
induction may lead to multidrug resistance. As scientific understanding of the mechanisms of
drug resistance increases, new treatments may be developed to counteract resistance.

Limitation of Chemotherapy

The Conventional chemotherapeutic agents that are used work by destroying the rapidly
diving cells, which is an important property of neoplastic cells. That is why chemotherapy
used to destroy normal healthy cells that divide sharpy such as cells present in the bone
marrow, macrophages digestive tract, and hair follicles .the main drawback of the
chemotherapy is that it cannot give selective action only to the cancerous cells. Because of
this common side effect result with the use of chemotherapeutic agents which include

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myelosupression (decreased production of white blood cells causing
immunosuppressant),mucositis ( inflammation of the lining of the digestive tract), alopecia
(hair loss),organ dysfunction ,and anemia or thrombocytopenia. Even chemotherapy agent
mostly cannot penetrates and reach the core of solid Tumor, thus failed to kill the cancerous
cells.

Chemotherapeutic agents mostly get washed out from the circulation as they being engulfed
by macrophages. Thus the remain in the circulation for a very short time making
chemotherapy completely ineffective as they or unable to interact with the cancer cells
.Other major problems reading the use of tradional chemotherapy are firstly , having cell
poor solubility another drugs makes them unable to penetrate. In the biological membranes.

Second problem is associated with p glycoprotein a multi drug resistance protein which is
over expressed on to the surface of the cancerous cells, preventing drug accumulation inside
the tumor, thus acting as an efflux pump and mostly mediates the development of resistance
to anticancerous drug , therefore the administered drugs remain unsuccessful and are unable
to bring the desired output.

TOXICITY OF CYTOTOXIC DRUGS

Cytotoxic drugs are more found on rapidly multiplying drugs.

1). Depression of bone marrow; they effect on granulocytopeia. They result in most serious
toxicity. The most common symptoms are bleeding and infections.

2). Lymphoreticular Tissue; Cell medicated as well as humoral immunity are affected by
lymphocytopenia immunity are effected by lymphocytopenia and inhibition lymphocyte
function.

3).Oral Cavity; Cytotoxic Drugs are highly epithelial cell turnover. In minor trauma, gums
and oral mucosa are regularly subjected.

4).GIT Diarrhea-decrease in the rate of gastrointestinal mucous form shedding of mucosa.

5).Skin – cells in hair follicles are damaged by Alopecia.

6).Gonads- Gonads inhabitance and are found in males& ovulation inhabitance and
amenorrhea are found in females.

7).Fetus- drugs given to pregnant women can damage the developing fetus.

8).Carcinogenicity- Greater frequency can be appeared in secondary cancer especially

leukemia.

9). Hyperuriccamia – They are very productive cell of purine metabolism.

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STRATEGIES AND MATERIALSUSED IN CANCER THERAPY

Various types of innovative methods of drugs delivery are being used in treatment of cancer.
Different varieties of synthesis polymer, protein, lipids and organic and inorganic particles
have been used for the development of cancer therapeutics. Drug encapsulation in a carrier
offers a number of advantages, when compared with the direct administration of bare chemo
drugs that is protection from degradation in the bloodstream, offers better drug solubility,
targeted drug delivery, decreased toxic side effect, also improve pharmacokinetic and
Pharmacodynamic drug properties and enhanced the drug stability. Today an effective library
of drug delivery vehicles has been developed that will vary in their sizes architectures and
surface physiochemical properties with targeting strategies.

Due to current progress in science and drug delivery allows us to controlled mechanisms so
as to be introduced in nanoparticle drug delivery system. This modification of nanoparticles
can be achieved by using stimuli responsive materials. These stimuli response delivery
system track the issues of controlled dose release of drug in response to various stimuli signal
specifically that is produced in the tumor microenvironment.

Currently the most common types of treatment that are given to the cancer patients include
chemotherapy, surgery, radiation or a combination of any of these treatments. But the
challengers that are associated with these traction treatments are non – specificity and
toxicity, that can be overcome by the use of nanoparticle in cancer therapy.

Conclusion

A plan for the diagnosis and treatment of cancer is a key component of any overall cancer
control plan. Its main goal is to cure cancer patients or prolong their life considerably,
ensuring a good quality of life. In order for a diagnosis and treatment programmed to be
effective, it must never be developed in isolation. It needs to be linked to an early detection
programmed so that cases are detected at an early stage, when treatment is more effective and
there is a greater chance of cure. It also needs to be integrated with a palliative care
programmed, so that patients with advanced cancers, who can no longer benefit from
treatment, will get adequate relief from their physical, psychosocial and spiritual suffering.
Furthermore, programmers should include an awareness-raising component, to educate
patients, family and community members about the cancer risk factors and the need for
taking preventive measures to avoid developing cancer.

Where resources are limited, diagnosis and treatment services should initially target all
patients presenting with curable cancers, such as breast, cervical and oral cancers that can be
detected early. They could also include childhood acute lymphatic leukemia, which has a
high potential for cure although it cannot be detected early. Above all, services need to be
provided in an equitable and sustainable manner. As and when more resources become
available, the programmed can be extended to include other curable cancers as well as
cancers for which treatment can prolong survival considerable.

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